The major long-term objective of these studies is to understand the regulation of plasma cholesterol levels and to determine how these levels can be effectively modified by drug therapy or by environmental manipulations. Such information would bear on the important health problems of atherosclerosis and cholesterol gallstone formation. In an initial group of investigations, methods will be developed for measuring absolute rates of both receptor-dependent and receptor-independent LDL uptake in all major organs of different animal species. Such studies will provide information on the quantitative importance of different organs for the uptake and degradation of circulating LDL and on the importance of the receptor-dependent and -independent processes. In a second group of investigations the circulating levels of LDL will be artificially altered in order to develop detailed kinetic curves for the transport of LDL into major organs by both the receptor-dependent and receptor-independent processes. These kinetic curves will provide data on the maximal transport rates and apparent Km values for the LDL uptake process and will make it possible to analyze how certain drugs and environmental manipulations alter LDL metabolism in specific organs. In a third group of investigations, detailed studies will be carried out on the mechanisms of regulation of LDL transport. In such investigations the rates of cholesterol synthesis in organs like the intestine, liver and extrahepatic tissues will be systematically altered under circumstances where both receptor-dependent and receptor-independent LDL transport will be assayed in order to explore the relationship between these two variables. In a fourth group of investigations the process responsible for the specific binding of high-density lipoproteins to endocrine cells will be further examined. In addition, the quantitative importance of cholesterol substrate derived from de novo synthesis, HDL or LDL for steroid hormone production will be assayed in the endocrine glands from different species. Finally, with the data available on the kinetics of LDL transport, it will be possible to elucidate the mechanisms of action of different drugs and dietary manipulations known to alter circulating plasma LDL levels. Taken together, the results of these studies will provide a much better understanding of the physiology of cholesterol balance and LDL metabolism in the intact animal and in man.